Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

Themis Thoudam, Dipanjan Chanda, Jung Yi Lee, Min-Kyo Jung, Ibotombi Singh Sinam, Byung-Gyu Kim, Bo-Yoon Park, Woong Hee Kwon, Hyo-Jeong Kim, Myeongjin Kim, Chae Won Lim, Hoyul Lee, Yang Hoon Huh, Caroline A. Miller, Romil Saxena, Nicholas J. Skill, Nazmul Huda, Praveen Kusumanchi, Jing Ma, Zhihong Yang, Min-Ji Kim, Ji Young Mun, Robert A. Harris, Jae-Han Jeon, Suthat Liangpunsakul () and In-Kyu Lee ()
Additional contact information
Themis Thoudam: Kyungpook National University
Dipanjan Chanda: Kyungpook National University
Jung Yi Lee: Kyungpook National University Hospital
Min-Kyo Jung: Korea Brain Research Institute
Ibotombi Singh Sinam: Kyungpook National University Hospital
Byung-Gyu Kim: Institute for Basic Science (IBS)
Bo-Yoon Park: Kyungpook National University
Woong Hee Kwon: Kyungpook National University Hospital
Hyo-Jeong Kim: Korea Basic Science Institute
Myeongjin Kim: Kyungpook National University
Chae Won Lim: Kyungpook National University Hospital
Hoyul Lee: Kyungpook National University
Yang Hoon Huh: Korea Basic Science Institute
Caroline A. Miller: Indiana University School of Medicine
Romil Saxena: Indiana University School of Medicine
Nicholas J. Skill: Louisiana State University Health Science Center
Nazmul Huda: Indiana University School of Medicine
Praveen Kusumanchi: Indiana University School of Medicine
Jing Ma: Indiana University School of Medicine
Zhihong Yang: Indiana University School of Medicine
Min-Ji Kim: Kyungpook National University Chilgok Hospital
Ji Young Mun: Korea Brain Research Institute
Robert A. Harris: Indiana University School of Medicine
Jae-Han Jeon: Kyungpook National University Chilgok Hospital
Suthat Liangpunsakul: Indiana University School of Medicine
In-Kyu Lee: Kyungpook National University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.

Date: 2023
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DOI: 10.1038/s41467-023-37214-4

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